Alterations in hypothalamic pituitary adrenal (HPA) functioning in Major Depressive Disorder (MDD) have been studied for decades. However, relatively little is known about the role of cortisol in psychological features of MDD. Extensive basic research shows that cortisol modulates core affective and cognitive processes (especially learning and memory) and their neural substrates. As of yet, little clinical research has applied this basic knowledge to the study of neural underpinnings of cognition and affect in depression. HPA alterations in depression are often characterized by deficient negative feedback, in which cortisol elevations are relatively ineffective in suppressing further HPA activation. Research from a number of sources suggests that in depressed individuals, brain glucocorticoid receptors (GR) in certain key regions may be relatively insensitive to the effects of cortisol. The proposed project will use pharmacological manipulation of cortisol in combination with functional magnetic resonance imaging (fMRI) to determine whether cortisol's effects on regional brain activity differ for depressed and healthy individuals, and how these effects on brain functioning mediate cortisol's effects both on psychological functioning and on HPA negative feedback. Furthermore, using pharmacological blockade of GR in depressed and healthy individuals, the proposed projects will test whether the effects of cortisol are mediated by GR. The candidate is a Clinical Psychologist, and has research background in 1) positron emission tomography studies of regional brain functioning in MDD and 2) the effects of cortisol on memory in healthy individuals. The candidate has proposed a training program that includes implementation of the proposed program of research, which requires training in each of the following areas: in depth HPA axis biology, corticosteroid receptor biology, pharmacological probes of corticosteroid functioning in clinical samples, pharmacological fMRI, and professional development and leadership skills. [unreadable] [unreadable]